The present invention relates to cyclic compounds which can be used in the treatment of dyslipidaemia, atherosclerosis and diabetes, to pharmaceutical compositions containing them and to processes for preparing these compounds.
The invention also relates to the use of these compounds for the production of medicinal products intended for the treatment of dyslipidaemia, atherosclerosis and diabetes.
In most countries, cardiovascular disease remains one of the main diseases and the main cause of mortality. About a third of men develop a major cardiovascular disease before the age of 60, women showing a lower risk (ratio of 1 to 10). This disease becomes even more prevalent with age (after the age of 65, women become just as vulnerable to cardiovascular disease as men). Vascular diseases such as coronary disease, cerebrovascular accidents, restenosis and peripheral vascular disease remain the main cause of mortality and handicap throughout the world.
Although the diet and the lifestyle can accelerate the development of cardiovascular diseases, a genetic predisposition leading to dyslipidaemia is a significant factor in cardiovascular attacks and death.
The development of atherosclerosis appears to be linked mainly to dyslipidaemia, which means abnormal levels of lipoproteins in the blood plasma. This dysfunction is particularly evident in coronary disease, diabetes and obesity.
The concept intended to explain the development of atherosclerosis has mainly been focused on the metabolism of cholesterol and on the metabolism of triglycerides.
However, since the research studies by Randle et al. (Lancet, 1963, 785-789), an original concept has been proposed: a glucose-fatty acid cycle or Randle cycle, which describes regulation of the equilibrium between the metabolism of lipids, in terms of triglycerides and cholesterol, and the oxidation of glucose. According to this concept, the inventors have developed an original programme, the aim of which is to find novel compounds which act simultaneously on the metabolism of lipids and glucose.
Fibrates are well-known therapeutic agents with a mechanism of action via the xe2x80x9cPeroxisome Proliferator Activated Receptorsxe2x80x9d. These receptors are the main regulators of lipid metabolism in the liver (PPARxcex1 isoform). In the last ten years, thiazolidinediones have been described as powerful hypoglycaemiant agents in animals and man. It has been reported that thiazolidinediones are powerful selective activators of another form of PPARs: PPARxcex3 (Lehmann et al., J. Biol. Chem., 1995, 270, 12953-12956).
The inventors have discovered a novel class of compounds which are powerful activators of the PPARxcex1 and PPARxcex3 isoforms. On account of this activity, these compounds have a substantial hypolipidaemiant and hypoglycaemiant effect.
The compounds of the invention correspond to formula I below: 
in which
X and Y represent, independently of each other, a methylene group; an oxygen or sulphur atom; or xe2x80x94NRaxe2x80x94 in which Ra represents a hydrogen atom, a (C1-C7)alkyl, (C6-C10)aryl group or a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, S and N; the said aryl group and the said heterocycle optionally being substituted with one or more radicals Z as defined below;
R represents a hydrogen atom; a (C1-C7)alkyl group; a phthalamido (C1-C7) alkyl group; (C3-C12) cycloalkyl; a group xe2x80x94(CH2)pxe2x80x94COORb in which p is an integer from 0 to 6 and Rb represents a hydrogen atom or a (C1-C7)alkyl group; a (C6-C10)aryl group; a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, S and N; a (C6-C10)aryl(C1-C7)alkyl group; it being understood that the aryl groups present in R and the said heterocycle are optionally substituted with one or more substituents chosen from a radical Z as defined below and a (C1-C7)alkylene chain;
R1 represents a hydrogen atom; a (C1-C7)alkyl group; (C1-C7)hydroxyalkyl; a (C6-C10)aryl group optionally substituted with one or more radicals W as defined below; a group xe2x80x94P(O) (OR8) (OR9) in which R8 and R9 are, independently, a hydrogen atom or a (C1-C7)alkyl group; a group xe2x80x94(CH2)txe2x80x94COORc in which t is an integer from 0 to 6 and Rc represents a hydrogen atom or a (C1-C7)alkyl group; a group xe2x80x94CONR10R11 in which R10 and R11 independently represent a hydrogen atom, a (C1-C7)alkyl group, a group RdOxe2x80x94COxe2x80x94(C1-C7)alkyl in which Rd represents H or (C1-C7)alkyl, or alternatively R10 and R11 together form a xe2x80x94(CH2) chain in which r is an integer equal to 4, 5 or 6;
R2 and R3 independently represent a hydrogen atom; a (C1-C7)alkyl group; (C3-C12)cycloalkyl; (C6-C10)aryl; (C6-C10)aryl(C1-C7)alkyl; a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S; or a fluorenyl group; the said aryl groups present in R2 or R3, the said heterocycle and the said fluorenyl optionally being substituted with one or more radicals Z as defined below;
or alternatively R2 and R3 together form a chain xe2x80x94(CH2)r1 in which r1 is an integer equal to 2, 3, 4 or 5;
or alternatively R2 and R3 together form the group (a): 
xe2x80x83in which A1 and A2 independently represent (C6-C10)aryl or a 5- to 10-membered aromatic heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from N, O and S, the said aryl group and the said heterocycle optionally bearing, in addition to the substituents R12 and R13, one or more other substituents chosen from the radicals Z as defined below; and in which R12 and R13 together form a chain
xe2x80x94(CH2)mxe2x80x94Exe2x80x94(CH2)nxe2x80x94 or xe2x80x94CHR14xe2x95x90CHR15xe2x80x94
in which m and n are, independently, an integer from 0 to 6; E represents a bond, O, S, xe2x80x94NRexe2x80x94, in which Re represents a hydrogen atom or (C1-C7)alkyl or alternatively E represents a (C1-C7)alkylene or (C6-C10)arylene chain or a 3- to 10-membered divalent heterocyclic radical comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S; and
R14 and R15 are chosen, independently, from a hydrogen atom, (C1-C7)alkyl and (C6-C10)aryl;
R4, R5, R6 and R7 independently represent a hydrogen atom; (C1-C7)alkyl; (C6-C10)aryl optionally substituted with one or more radicals Z as defined below; or a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S, the said heterocycle optionally being substituted with one or more radicals Z as defined below;
Z is chosen from a halogen atom; a hydroxyl group; nitro; cyano; phenyl; phenyl (C1-C7) alkyl; trifluoromethoxy; (C1-C7) alkyl optionally substituted with one or more halogen atoms; (C1-C7)alkoxy; (C1-C7)alkylthio; (C2-C7)acylthio; (C1-C7)alkylsulphonyl; (C1-C7) alkylsulphinyl; carbamoyl; Nxe2x80x94(C1-C7)alkylcarbamoyl; N,N-di(C1-C7)alkylcarbamoyl; (C1-C7) alkylamino; di( C1-C7) alkylamino; a group xe2x80x94Axe2x80x94COORf in which Rf represents a hydrogen atom or a (C1-C7)alkyl group and A represents (C1-C7)alkylene, (C2-C7) alkenylene, (C1-C7)oxyalkylene in which the alkylene chain is linked to the group COORf or alternatively A is nothing; or a group xe2x80x94Bxe2x80x94P(O)(ORx)(ORy) in which B takes one of the meanings given for A above and Rx and Ry independently take one of the meanings given for Rf above;
W represents xe2x80x94Gxe2x80x94COORg in which G represents (C1-C7)alkylene, (C2-C7)alkenylene, (C1-C7)oxyalkylene in which the alkylene chain is linked to the group COORg or alternatively G is nothing, and Rg represents a hydrogen atom or a (C1-C7)alkyl group; or alternatively W represents
xe2x80x94Dxe2x80x94P(O)(ORz)(ORt) in which D takes one of the meanings given above for G and Rz and Rt independently take one of the meanings given above for Rg;
and the pharmaceutically acceptable salts thereof,
xe2x80x83it being understood that
(i) when R2, R3, R5 and R7 represent a hydrogen atom; X and Y represent an oxygen atom; R4 represents methyl; and R6 represents a hydrogen atom or a methyl group, then R1 and R, together with the carbon atom which bears them, do not form any of the following divalent radicals: 
and (ii) when R4, R5, R6 and R7 represent a hydrogen atom; X and Y represent O; and R represents pyridyl, piperidyl or substituted piperidyl; then R1 does not represent optionally substituted phenyl.
Formula I encompasses all the types of geometrical isomers and stereoisomers of the compounds of formula: 
The physiologically acceptable salts of the compounds of formula (I) comprise the salts formed with metals and in particular with alkali metals, alkaline-earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminum) or with bases such as aqueous ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids (such as lysine or arginine) or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol).
According to the invention, the term xe2x80x9calkylxe2x80x9d denotes a linear or branched hydrocarbon-based radical such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl or heptyl. When the alkyl group is substituted with one or more halogen atoms, it preferably represents perfluoroalkyl and in particular pentafluoroalkyl.
The term xe2x80x9calkoxyxe2x80x9d denotes an alkyl group as defined above linked to an oxygen atom. Examples of this are the methoxy, ethoxy, isopropyloxy, butoxy and hexyloxy radicals.
The term xe2x80x9ccycloalkylxe2x80x9d denotes saturated hydrocarbon-based groups which can be mono- or polycyclic and comprise from 3 to 12 carbon atoms, preferably from 3 to 8. The groups more particularly preferred are monocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine atom.
The term xe2x80x9carylxe2x80x9d represents a mono- or bicyclic aromatic hydrocarbon-based group comprising 6 to 10 carbon atoms, such as phenyl or naphthyl.
The term xe2x80x9cheterocyclexe2x80x9d denotes a mono- or bicyclic ring of aromatic or non-aromatic nature comprising 3 to 10 ring members, 1 to 4 of which are occupied by identical or different hetero atoms chosen from oxygen, sulphur and nitrogen, such as, for example, aziridinyl, oxiranyl, oxazolyl, furyl, tetrahydrofuryl, benzothiazolyl, pyrimidinyl, pyridazinyl, piperidinyl, quinolyl, tetrahydroquinolyl, tetrazolyl, phthalazinyl, purinyl, indolyl, chromenyl, chromanyl, isochromanyl and pyrrolyl radicals.
The term xe2x80x9cheterocyclexe2x80x9d preferably denotes thienyl, furyl or pyrrolyl.
The phthalamido (C1-C7)alkyl group preferably denotes the radical of formula: 
When R represents (C6-C10)aryl, (C6-C10)aryl(C1-C7)alkyl or a heterocycle, the aryl group and the heterocycle can be substituted with a (C1-C7)alkylene chain. In this case, the two free valencies of the said alkylene chain are linked to two members of the aryl group, or of the heterocycle, respectively. Denoting the aryl group or the heterocycle as C, the structure formed can be represented in the following manner: 
in which nxe2x80x2 represents 1, 2, 3, 4, 5, 6 or 7.
When R1 represents a group xe2x80x94CONR10R11 in which R10 and R11 together form a chain xe2x80x94(CH2)rxe2x80x94, R10, R11 and the nitrogen atom which bears them together form a 5- to 7-membered nitrogen ring comprising an endocyclic nitrogen atom.
When R2 or R3 represents fluorenyl, it is preferably the 9-fluorenyl group.
When R2 and R3 together form a xe2x80x94(CH2)r1xe2x80x94 chain, R2 and R3 and the carbon atom which bears them together preferably form a cyclopropyl group.
The benzyl group may be mentioned as a preferred (C6-C10)aryl(C1-C7)alkyl group.
When R2 and R3 together form the group (a): 
in which A1, A2, R12 and R13 are as defined above, A1 and A2 are hydrocarbon-based or heterocyclic rings comprising at least one ethylenic unsaturation  greater than Cxe2x95x90C less than  and bearing at least the radical R12, or R13, respectively, as substituent, but possibly bearing other substituents chosen from the radicals Z as defined above.
It is preferred for A1 and A2 to represent phenyl optionally substituted with one to four substituents Z.
It will be noted that the schematic representation of A1 and A2 given above means that A1 and A2 are linked to the same carbon atom (carbon 1) via carbon-carbon single bonds (bond 1-2, or 1-2xe2x80x2, respectively), the carbon atom of the ring A1, or of the ring A2, respectively, engaged in this bond (2, or 2xe2x80x2, respectively) being of sp2 type, i.e. forming a double bond with a neighbouring carbon atom, located in an a position (carbon 3, or 3xe2x80x2, respectively).
The substituent R12 is located in any position on the ring A1, and similarly R13 is linked to the ring A2 via any of the ring members of A2. However, it is preferred for R12 and R13 to substitute, respectively, the sp2 carbons in the a position, i.e. the carbons of type (3 and 3xe2x80x2) as represented in the above scheme.
According to the invention, preferred meanings of the group (a) are: 
The term xe2x80x9cacylxe2x80x9d means a (C1-C7)alkylcarbonyl radical and the term xe2x80x9cacylthioxe2x80x9d means a (C1-C7)alkylthiocarbonyl radical of formula: 
According to the invention, the term xe2x80x9calkenylenexe2x80x9d radical moreover means a divalent hydrocarbon-based radical bearing one or more ethylenic double bonds, such as, for example, xe2x80x94CHxe2x95x90CHxe2x80x94 or: 
The xe2x80x9ccarbamoylxe2x80x9d radical denotes the monovalent radical of formula xe2x80x94COxe2x80x94NH2. The xe2x80x9c(C1-C7)alkylcarbamoylxe2x80x9d radical denotes a carbamoyl radical substituted with a C1-C7 alkyl group on the nitrogen atom, and the xe2x80x9cdi(C1-C7)alkylcarbamoylxe2x80x9d radical denotes a carbamoyl radical substituted on the nitrogen atom with two C1-C7 alkyl groups.
The xe2x80x9c(C1-C7)alkylaminoxe2x80x9d radical denotes an amino group substituted on the nitrogen atom with a (C1-C7)alkyl radical and the xe2x80x9cdi(C1-C7)alkylaminoxe2x80x9d radical denotes an amino group substituted on the nitrogen atom with two (C1-C7)alkyl radicals.
U.S. Pat. No. 4,056,540 describes compounds such as 4-phenyl-1,3-benzodioxane bearing a carboxylic function in position 2 of the benzodioxane ring, which have anticonvulsive or antiarrhythmic activity.
More recently, [4H]-1,3-benzodioxine-2-carboxylic acids and esters endowed with hypolipaemiant activity have been described in Eur. J. Med. Chem. Ther., 1983, 67.
However, the benzodioxane structure of these compounds differs entirely from the structure of the compounds of the invention.
Tetrahedron Asymmetry, vol. 3, No. 8, 1075-1086, 1992 describes the asymmetric synthesis of chiral ketals and in particular the synthesis of certain compounds of formula: 
in which R0 represents xe2x80x94COOCH3 or xe2x80x94CH2OH.
However, that document makes no reference at all to the pharmacological value of these compounds. In addition, J. Med. Chem., 1969, 51 describes anti-inflammatory compounds of 2-aryl-2-xcex1-piperidyl-1,3-dioxane type. Among these compounds, those corresponding to one of the following formulae are relatively close to the compounds of the invention: 
in which Rxe2x80x2 represents a hydrogen atom, a chlorine atom or a methoxy group; R01 and R02 represent either a hydrogen atom, an alkyl group or an aryl group; and R03 is a methyl or methoxy group.
However, the anti-inflammatory activity of these compounds is in no way comparable with the hypolipidaemic and hypoglycaemic activity of the compounds of the invention.
Among the compounds of the invention, certain are preferred.
A first group of preferred compounds consists of the compounds of formula I as defined above for which X and Y represent an oxygen atom.
A second group of preferred compounds consists of the compounds of formula I in which R4, R5, R6 and R7 represent a hydrogen atom.
A third group of preferred compounds consists of the compounds of formula I in which:
R represents a hydrogen atom; a (C1-C7)alkyl group; a phthalamido (C1-C7)alkyl group; (C3-C12)cycloalkyl; a heterocycle as defined above for formula I; a (C6-C10)aryl group; or a (C6-C10)aryl(C1-C7)alkyl group; it being understood that the aryl groups present in R and the said heterocycle are optionally substituted with one or more substituents chosen from a (C1-C7)alkylene chain; a halogen atom; a phenyl group; (C1-C7)alkyl optionally substituted with one or more halogen atoms; (C1-C7)alkoxy; or a group xe2x80x94Axe2x80x94COORf in which A and Rf are as defined above for formula I;
R1 represents a hydrogen atom; a (C1-C7)alkyl group; xe2x80x94(CH2)txe2x80x94COORc in which t and Rc are as defined above for formula I;
R2 and R3 independently represent a hydrogen atom; a group (C6-C10)aryl or (C6-C10)aryl(C1-C7)alkyl; the aryl groups present in R2 and R3 optionally being substituted with one or more radicals chosen from a halogen atom; a (C1-C7)alkyl group optionally substituted with one or more halogen atoms; (C1-C7)alkoxy; Nxe2x80x94(C1-C7)alkyl-carbamoyl; (C1-C7)alkylamino; nitro; cyano; and xe2x80x94Axe2x80x94COORf in which A and Rf are as defined above for formula I;
or alternatively R2 and R3 together form the group (a) as defined above for formula I in which A1 and A2 represent a phenyl group; and R12 and R13 together form a chain xe2x80x94(CH2)mxe2x80x94Exe2x80x94(CH2)nxe2x80x94 in which m, n and E are as defined above for formula I, or a chain xe2x80x94CHR14xe2x95x90CHR15xe2x80x94 in which R14 and R15 are as defined above for formula I;
or alternatively R2 and R3 together form a chain xe2x80x94(CH2)r1 in which r1 is an integer equal to 2, 3, 4 or 5.
A fourth group of preferred compounds consists of the compounds of formula I in which
R represents a hydrogen atom; a (C1-C7)alkyl group; (C3-C12)cycloalkyl; xe2x80x94(CH2)pxe2x80x94COORb in which p and Rb are as defined above for formula I; xe2x80x94(C6-C10)aryl or a heterocycle as defined above for formula I; it being understood that the said aryl group and the said heterocycle are optionally substituted with one or more substituents chosen from a halogen atom; a (C1-C7)alkyl group; (C1-C7)alkoxy; or xe2x80x94Axe2x80x94COORf in which A and Rf are as defined above for formula I;
R1 represents a (C1-C7)alkyl or xe2x80x94(CH2)txe2x80x94COORc group in which t and Rc are as defined above for formula I; a group xe2x80x94CONR10R11 in which R10 and R11 are as defined above for formula I;
R2 and R3 together form the group (a) as defined above for formula I in which A1 and A2 represent phenyl; and R12 and R13 together form a chain xe2x80x94(CH2)mxe2x80x94Exe2x80x94(CH2)nxe2x80x94 in which m and n represent 0 and E represents a bond.
Among these compounds, those for which
R represents a hydrogen atom; (C1-C4)alkyl; xe2x80x94(CH2)pxe2x80x94COORb in which p represents 1, 2 or 3 and Rb represents a hydrogen atom or (C1-C4) alkyl; phenyl optionally substituted with a radical chosen from halogen, (C1-C4) alkyl, (C1-C4) alkoxy or xe2x80x94Axe2x80x94COORf in which A represents (C1-C4)alkylene or a bond and Rf represents H or (C1-C4)alkyl; furyl; thienyl; or pyrrolyl;
R1 represents a (C1-C4)alkyl group; or alternatively xe2x80x94(CH2)txe2x80x94COORc in which t represents 0, 1, 2, 3 or 4 and Rc represents a hydrogen atom or (C1-C4) alkyl;
R2 and R3 together form the group (a) as defined above for formula I, A1 and A2 representing phenyl and R12 and R13 together forming a bond or a (C1-C4)alkylene chain
are particularly preferred.
A fifth group of preferred compounds consists of the compounds of formula I in which
R represents (C6-C10)aryl optionally substituted with a halogen atom;
R1 represents xe2x80x94COORc in which Rc is as defined above for formula I;
R2 and R3 together form the group (a) as defined above for formula I in which A1 and A2 represent phenyl; and R12 and R13 together form a chain xe2x80x94(CH2)mxe2x80x94Exe2x80x94(CH2)nxe2x80x94 in which m and n represent 0 and E represents a bond, O or S.
A sixth group of preferred compounds consists of the compounds of formula I in which
R represents (C6-C10)aryl optionally substituted with a halogen atom;
R1 represents xe2x80x94COORc in which Rc is as defined above for formula I;
R2 and R3 together form the group (a) as defined above for formula I in which A1 and A2 represent phenyl; and R12 and R13 together form a chain xe2x80x94CHR14xe2x95x90CHR15xe2x80x94 in which R14 and R15 are as defined above for formula I.
A seventh group of preferred compounds consists of the compounds of formula I for which at least one of the radicals R or R1 bears a carboxylic group optionally in esterified form or in the form of amide. Among these compounds, the preferred ones are those for which R represents xe2x80x94(CH2)pxe2x80x94COORb [lacuna] and Rb are as defined above for formula I; or alternatively R represents (C6-C10)aryl or (C6-C10)aryl(C1-C7) alkyl in which the aryl group present in R is substituted with a radical xe2x80x94Axe2x80x94COORf in which A and Rf are as defined above for formula I; or alternatively R1 represents xe2x80x94(CH2)txe2x80x94COORc in which t and Rc are as defined above for formula I; or alternatively R1 represents (C6-C10)aryl substituted with xe2x80x94Gxe2x80x94COORg in which G and Rg are as defined above for formula I; or alternatively R1 represents xe2x80x94CONR10R11 in which R10 and R11 are as defined above for formula I.
Among this seventh group of preferred compounds, those satisfying at least one of the following conditions are more particularly preferred:
X and Y represent an oxygen atom,
R4 to R7 represent a hydrogen atom;
only one of the groups R or R1 bears a carboxylic group which is optionally esterified or in the form of amide, the other being as defined for the third group of preferred compounds above; and R2 and R3 being as defined for the third group of preferred compounds;
only one of the groups R or R1 bears a carboxylic group which is optionally esterified or in the form of amide, the other being as defined for the fourth group of preferred compounds above; and R2 and R3 being as defined for the fourth group of preferred compounds:
When R bears a carboxylic group optionally in ester form, it preferably represents phenyl substituted with xe2x80x94COOH; with xe2x80x94Axe2x80x94COORf in which A represents (C2-C5) alkenylene and Rf represents H or (C1-C4)alkyl; or with (C1-C4)alkoxycarbonyl.
When R1 bears a carboxylic group optionally in the form of ester or amide, it preferably represents xe2x80x94(CH2)txe2x80x94COORc in which t is 0, 1, 2, 3 or 4 and Rc is H or (C1-C4)alkyl; or alternatively xe2x80x94CONR10R11 in which R10 and R11 are as defined above for formula I, but in which R10 and R11 do not together form a chain xe2x80x94(CH2)rxe2x80x94.
Examples of compounds of the invention are the following:
methyl 2-methyl-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-methyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-(4-methoxyphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(4-methoxyphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-(4-methylphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(4-methylphenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 5,5-diphenyl-2-thiophen-2-yl[1,3]dioxane-2-carboxylate 5,5-diphenyl-2-thiophen-2-yl[1,3]dioxane-3-carboxylic acid ethyl 5,5-diphenyl[1,3]dioxane-2-carboxylate 5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2,5,5-triphenyl[1,3]dioxane-2-carboxylate 2,5,5-triphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-(4-fluorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(4-fluorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 5,5-diphenyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,3]dioxane-2-carboxylate ethyl 2-furan-2-yl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl 2-(3-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(3-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-isopropyl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl 2-phenethyl-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-phenethyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-biphenyl-4-yl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl 2-(3,4-dichlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(3,4-dichlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic [lacuna] 2-biphenyl-4-yl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2-[2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]acetate 2-[2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]acetic acid ethyl 2-cyclohexyl-5,5-diphenyl[1,3]dioxane-2-carboxylate ethyl 2-(5,5-diphenyl[1,3]dioxan-2-yl)benzoate 2-(5,5-diphenyl[1,3]dioxan-2-yl)benzoic acid 5,5-diphenyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,3]dioxane-2-carboxylic acid 2-furan-2-yl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid 2-(1-naphthyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid 2-(1-naphthyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid 2-isopropyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid [2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]methanol 2-cyclohexyl-5,5-diphenyl[1,3]dioxane-2-carboxylic acid [2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxan-2-yl]1-piperidyl ketone 2-[(2-methyl-5,5-diphenyl[1,3]dioxan-2-yl)methyl]isoindole-1,3-dione ethyl 5-[4-(5,5-diphenyl[1,3]dioxan-2-yl)phenyl]-3-methylpenta-2,4-dienoate 5-[4-(5,5-diphenyl[1,3]dioxan-2-yl)phenyl]-3-methylpenta-2,4-dienoic acid 2-(ethoxycarbonylmethylaminocarbonyl)-2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane 2-carboxymethylaminocarbonyl-2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane ethyl 5,5-diphenyl-2-(4-trifluoromethylphenyl)-[1,3]dioxane-2-carboxylate 2-[4-(5,5-diphenyl[1,3]dioxan-2-yl)phenoxy]-2-methylpropionic acid 2-(4-trifluoromethylphenyl)-5,5-diphenyl[1,3]dioxan-2-ylcarboxylic acid ethyl 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylate 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acid ethyl 2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylate 2-(4-chlorophenyl)-5,5-bis(4-fluorophenyl)-[1,3]dioxane-2-carboxylic acid ethyl 2-(4-chlorophenyl)-5,5-bis(3-trifluoromethyl-phenyl)-[1,3]dioxane-2-carboxylate 2-(4-chlorophenyl)-5,5-bis(3-trifluoromethylphenyl)-[1,3]dioxane-2-carboxylic acid ethyl 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,5xe2x80x2-5xe2x80x2H-dibenzo[a,d]cycloheptene]-2-carboxylate 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,5xe2x80x2-5xe2x80x2H-dibenzo[a,d]cycloheptene]-2-carboxylic acid 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9xe2x80x2-xanthene]-2-carboxylic acid 2-(4-chlorophenyl)spiro[1,3-dioxane-5,9xe2x80x2-xanthene]-2-carboxylic acid ethyl 2-(4-chlorophenyl)-5-(9H-fluoren-9-yl)-[1,3]dioxane-2-carboxylate ethyl 2xe2x80x2-(4-chlorophenyl)spiro[cyclobutane-1,5xe2x80x2-[1,3]dioxane]-2xe2x80x2-carboxylate 2-(4-chlorophenyl)spiro[cyclobutane-1,5xe2x80x2-[1,3]dioxane]-2xe2x80x2-carboxylic acid 5,5-dibenzyl-2-(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acid methyl 2-methylspiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate 2-methylspiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid ethyl 2-(2-methylspiro[[1,3]dioxane-5,9xe2x80x2-fluoren]-2-yl)acetate 2-(2-methylspiro[[1,3]dioxane-5,9-fluoren]-2-yl)acetic acid methyl 2-(2-methoxycarbonylethylspiro[[1,3]dioxane-5,9xe2x80x2-fluoren]-2-yl)acetate 2-(2-carboxyethylspiro[[1,3]dioxane-5,9xe2x80x2-fluoren]-2-yl)acetic acid methyl 4-(2-methylspiro[[1,3]dioxane-5,9xe2x80x2-fluoren]-2-yl)benzoate butyl spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid methyl 2-phenylspiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate 2-phenylspiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid ethyl 2-[4-methylphenyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate ethyl 2-[4-methoxyphenyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate 2-[4-methoxyphenyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid ethyl 2-[4-chlorophenyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate 2-[4-chlorophenyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid ethyl 2-[2-thienyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate 2-[2-thienyl]spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid 2-(4-chlorophenyl)-5,5-diphenyl[1,3]oxazinane
Among these compounds, the following are particularly preferred:
ethyl 2-(4-chlorophenyl]-5,5-diphenyl[1,3]dioxane-2-carboxylate 2-(4-chlorophenyl)-5,5-diphenyl[1,3]dioxane-2-carboxylic acid ethyl 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylate 2,5,5-tris(4-chlorophenyl)-[1,3]dioxane-2-carboxylic acid ethyl 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylate 2-(4-chlorophenyl)spiro[[1,3]dioxane-5,9xe2x80x2-fluorene]-2-carboxylic acid.
The compounds of the invention and those defined in points (i) and (ii) above can be prepared using any of the following processes.
In general, the compounds of formula I can be prepared by reaction of a compound of formula: 
in which X, Y and R2 to R7 are as defined above for formula I, it being understood that X or Y can also represent a nitrogen atom substituted with a function which is a precursor of the radical Ra, with a ketone of formula III:
RCOxe2x80x94R1
in which R and R1 are as defined above for formula I.
When, in formula I, X and Y are an oxygen atom, the processes A, B, C or D can be used.
Process A:
A diol of formula II 
in which R2 to R7 are as defined for formula I, is reacted with a carbonyl derivative of formula III:
RCOxe2x80x94R1
in which R and R1 are as defined above for formula I, to give a compound of formula I in which X and Y represent an oxygen atom.
The reaction used is a cyclization reaction. This reaction is carried out under the standard conditions, either in the presence of a specific catalyst as described in:
S. Fukusawa et al., Synlett, 1995, 1077.
G. C. G. Pals, J. Chem. Research, 1996, 426.
B. P. Bandgar, Synth. Commun., 1997, 27(4), 627.
K. Ishihara, Synlett, 1987, 839.
S. B. Lee, Synthesis, 1991, 368
or in the absence of a catalyst, as described in F. A. J. Meskens, Synthesis, 1981, 501.
H. Suemune et al., Chem. Pharm. Bull., 1990, 38(11), 3155.
The reaction is typically carried out in an aprotic solvent which forms an azeotrope with water, such as toluene, at a temperature of from 50 to 150xc2x0 C., better still from 90 to 120xc2x0 C., in the presence of an excess of compound III. The molar ratio of compound III to the diol II will preferably be between 1.1 and 2, for example between 1.3 and 1.7.
In order to increase the yields, it is recommended to react the diol with the carbonyl compound in the presence of an acid catalyst such as para-toluenesulphonic acid, while removing the water from the reaction medium.
By way of example, the diol II may be reacted with the carbonyl derivative III in the presence of 0.2 equivalent of para-toluenesulphonic acid at the reflux point of toluene in Dean-Stark apparatus for 6 to 8 hours.
As a variant, the reaction can be carried out in a halogenated aliphatic hydrocarbon at a temperature of between 15 and 30xc2x0 C. in the presence of a Lewis acid. In this case, it is preferable for the molar ratio of the diol II to the carbonyl derivative III to range between 1.5 and 3, better still between 1.8 and 2.2.
By way of example, the diol II may be reacted with two equivalents of the derivative III in methylene chloride in the presence of one equivalent of BF3-etherate at room temperature for 12 to 48 hours.
Process B:
The compounds of formula I in which X and Y represent an oxygen atom can be prepared by reacting an alkali metal or alkaline-earth metal salt of a diol of formula II: 
in which R2 to R7 are as defined for I above, with a dihalo compound of formula IV: 
in which R and R1 are as defined for I above and X represents a halogen atom.
The metal salt of the diol II used as reagent is a salt in which the two hydroxyl functions are salified, either with the same metal cation M2+ of an alkaline-earth metal, or with two cations M+ of an alkali metal. It is preferred to carry out this reaction starting with an alkali metal salt and in particular the sodium salt.
According to a preferred embodiment of the invention, the metal salt is formed in situ in the reaction medium by the action of a metal hydride (and for example a sodium hydride) on the diol of formula II.
The reaction of the salt of the diol II with compound IV is preferably carried out in a polar aprotic solvent, such as an ether, at a temperature of between 15 and 30xc2x0 C., preferably in a slight excess of the metal salt of the diol II.
In order to increase the yields, the process will be performed, for example, in the presence of a crown ether as taught in Eur. J. Med. Chem. Chim. Ther. 1983, 67.
By way of example, 1.1 to 1.5 equivalents of the diol II are reacted with compound IV in which X represents chlorine, in anhydrous dioxane as solvent, in the presence of sodium hydride and 18-crown-6 at room temperature (20xc2x0 C.).
Process C:
The compounds of formula I in which X and Y represent an oxygen atom can also be obtained by transacetalization reaction, and more specifically by reacting the diol of formula II: 
in which R2 to R7 are as defined above for formula I, with a ketal of formula V: 
in which R and R1 are as defined above for formula I and R16 and R17 independently represent (C1-C7)alkyl or together form an alkylene chain of xe2x80x94(CH2)rxe2x80x2xe2x80x94 type in which rxe2x80x2 is an integer equal to 4, 5 or 6.
This reaction is preferably carried out in an aprotic solvent which forms an azeotrope with water, such as toluene, at a temperature of between 80 and 150xc2x0 C., for example at a temperature of between 90 and 120xc2x0 C. In order to increase the yields, it is desirable to perform the process in the presence of an excess of the diol of formula II (1.5 to 3 equivalents, preferably 1.8 to 2.2 equivalents) and of an acid catalyst, such as para-toluenesulphonic acid.
Inspiration may be taken from J. Am. Chem. Soc. 1958, 80, 6613.
By way of example, two equivalents of the diol II are reacted with one equivalent of compound V in the presence of 0.2 equivalent of para-toluenesulphonic acid in toluene maintained at reflux in Dean-Stark apparatus for 1 to 4 hours.
Process D:
The compounds of formula I in which X and Y represent an oxygen atom can be synthesized from the diols of formula II by forming the intermediate silyl derivatives according to reaction scheme 3 below: 
Scheme 3
In this scheme, R and R1 to R7 are as defined for formula I and T1 to T3 independently represent (C1-C4) alkyl.
According to this process, the disilyl derivative XI is prepared in a conventional manner. To do this, a person skilled in the art will refer, for example, to Tetrahedron 1994, 50, 42, 12143 and Chem. Lett. 1994, 263. The disilyl derivative XI is preferably formed in situ in the presence of the ketone III with which it reacts as it is formed. These two reactions are, in this case, preferably carried out in a polar aprotic solvent such as a halogenated aliphatic hydrocarbon. The molar ratio of the ketone III to the diol II is preferably between 1.1 and 2, better still between 1.3 and 1.7. The silylation is carried out, for example, by the action of an alkoxytrialkylsilane derivative (in which the alkyl parts are C1-C6). Preferably, a large excess of alkoxytrialkylsilane is reacted with the diol II in the presence of trifluoromethanesulphonate as catalyst. The molar ratio of the alkoxytrialkylsilane to the diol is, for example, between 2 and 6, better still between 3 and 5.
The temperature of the reaction medium is usually maintained between xe2x88x9240 and xe2x88x9210xc2x0 C.
By way of example, 1 equivalent of the ketone of [sic] III can be reacted with 1.3 equivalents of the diol II in anhydrous methylene chloride in the presence of 4 equivalents of isopropoxytrimethylsilane at temperatures of about xe2x88x9220xc2x0 C. and in the presence of 0.01 equivalent of trimethylsilyl trifluoromethane-sulphonate. The reaction time is typically about 3 hours.
The compounds of formulae III, IV and V are commercially available or easily prepared from active compounds by carrying out standard methods of organic chemistry.
For the synthesis of the acetals of formula V, a person skilled in the art may also refer to Synthesis 1983, 203.
Certain diols of formula II are described in the literature.
The diols of formula II can be obtained by carrying out any of the processes a), b) or c) below.
Process a).
The reaction scheme is represented below 
In this scheme, A1, A2, R12 and R13 are as defined for formula I and Alk represents (C1-C6)alkyl.
To synthesize the epoxide VII from the ketone VIII, a person skilled in the art may be inspired by the research described in:
J. Am. Chem. Soc. 1958, 80, 6389 or J. Am. Chem. Soc. 1931, 53, 205.
The ketone of formula VIII may, for example, be reacted with a compound of formula IX: 
in which Grp represents a leaving group (such as a chlorine atom) and Alk represents (C1-C6)alkyl in the presence of a base such as an alkali metal hydride or an alkali metal alkoxide. The reaction is preferably carried out in a polar aprotic solvent, such as an ether, at a temperature not exceeding 45xc2x0 C. Since the reaction is exothermic in certain cases, the reaction medium should be cooed during the reaction. An excess of the compound IX relative to the compound VIII will advantageously be used. A molar ratio of compound IX to compound VIII of between 1.2 and 2 is appropriate.
By way of example, compound VIII will be reacted with 1.5 equivalents of ethyl chloroacetate in the presence of sodium hydride or sodium ethoxide in tetrahydrofuran, the reaction medium being maintained at a temperature below 45xc2x0 C.
The aldehyde of formula VI is obtained from the epoxide VII in a conventional manner. Reference may be made, for example, to J. Med. Chem. 1968, 11, 380.
In general, the epoxide of formula VII is treated, in step 2, with a base such as potassium hydroxide at a temperature of between 15 and 120xc2x0 C. For example, when Alk represents ethyl, the epoxide VII is refluxed in the presence of KOH for 8 hours.
In order to convert the aldehyde obtained of formula VI into the diol of formula II, the process will be performed as indicated in J. Med. 1969, 12, 462 and J. Am. Chem. Soc. 1949, 2031.
By way of example, the diol II is obtained by treating the aldehyde VI with formaldehyde in aqueous solution (from 1.2 to 2 equivalents of formaldehyde) in the presence of a base such as potassium carbonate (from 1 to 2 equivalents). The reaction temperature is advantageously between 15 and 130xc2x0 C., preferably between 80 and 120xc2x0 C.
The ketones of formula VIII are commercially available or readily prepared from commercial compounds.
Process b):
Another way of performing the process is illustrated in scheme 5 below. 
Starting with the ketone VIII, the aldehyde VI is prepared by forming the intermediate epoxide X by carrying out a process similar to the one illustrated in J. Org. Chem. 1972, 35, 25, 4075. In order to convert the aldehyde VI into the diol of formula II, the process is performed as described above for process a). Typically, the aldehyde VI is reacted in ethanol with, for example, 0.2 mol of aqueous 37% formaldehyde solution in the presence of a base which can be potassium carbonate (0.05 mol) at reflux for 20 hours. An amount of water representing about ⅕ of that of ethanol will advantageously be added to the medium.
Process c):
According to a third variant, the diol of formula II can be obtained according to reaction scheme 6 below, in which Alk represents (C1-C6)alkyl and A1, A2, R12 and R13 are as defined above for formula I: 
The ester XI can be metallated by the action of butyllithium in tetrahydrofuran at a temperature of between xe2x88x9270 and xe2x88x9230xc2x0 C. The reaction mixture is then treated with gaseous formaldehyde at a temperature of from 0 to 25xc2x0 C., which gives the xcex1-hydroxymethyl derivative. This compound is reduced by the action of a suitable reducing agent, in a conventional manner. Lithium aluminum hydride may be mentioned as a reducing agent. In this case, the reduction is complete after two hours, the reaction medium being maintained at a temperature below 10xc2x0 C.
Certain compounds of formula II are novel. According to one of its aspects, the invention relates to the diols of formula II chosen from:
2,2-bis(4-fluorophenyl)propane-1,3-diol;
2,2-bis(3-trifluoromethylphenyl)propane-1,3-diol;
5-hydroxymethyl-5H-dibenzo[a,d]cyclohepten-5-ylmethanol; and
(9-hydroxymethyl-9H-xanthen-9-yl)methanol which are novel.
The esters of formula XI are commercial products or are readily prepared from commercial products.
Process E below allows the formation of the compounds of formula I in which X represents O and Y represents S.
Process E
According to this process, a compound of formula XII: 
in which R2 to R7 are as defined above for formula I, is reacted with the ketone of formula III
RCOxe2x80x94R1xe2x80x83xe2x80x83III
This reaction may be carried out by analogy with the processes described in the following publications, which also illustrate the preparation of the compounds of formula XII:
E. L. Eliel et al., J. Am. Chem. Soc., 1962, 84, 2377
A. J. Liepa et al., Aust. J. Chem., 1986, 39, 1747
R. Caputo et al., Synthesis, 1987, 386
B. Burczyk et al., Synthesis, 1982, 831
F. E. Ziegler et al., Tetrahedron Lett., 1978, 31, 2767
A technique based on the one described in Caputo et al., Synthesis, 1987, 386 consists in reacting the ketone III with the compound XII in the presence of polystyryldiphenyliodophosphonium iodide in a polar aprotic solvent such as acetonitrile, at a temperature of between 10 and 40xc2x0 C., preferably at room temperature (about 20xc2x0 C. ). Using anhydrous acetonitrile at 20xc2x0 C., the reaction is complete within 30 minutes to 2 hours.
For the synthesis of the compounds of formula I in which X and Y are a group xe2x80x94NRaxe2x80x94, process F below may be used.
Process F
According to this process, the diamine XIII: 
in which R2 to R7 are as defined for formula I and R18 and R19 independently have one of the meanings given for Ra in formula I or represent a precursor radical leading to any of these meanings, is reacted with the ketone of formula III:
RCOxe2x80x94R1xe2x80x83xe2x80x83III
The operating conditions for carrying out this reaction will be readily determined by a person skilled in the art, who may perform the process, for example, as taught in:
P. M. Hardy et al., J. Chem. Soc., Perkin Trans. 1, 1977, 1954
T. Araki et al., Macromolecules, 1995, 21(7), 1988
Carpentier et al., Tetrahedron, 1985, 41(18), 3803
R. Gosmini et al., Synlett, 1991, 111
A. Alexakis et al., Synlett, 1991, 625
M. Gray et al., Synlett, 1991, 729
T. Okawara et al., J. Chem. Soc., Chem. Commun., 1990, 20, 1385
Typically, the reaction of XIII with III is carried out in an aprotic solvent such as an aromatic hydrocarbon at a temperature of from 80 to 150xc2x0 C., preferably from 90 to 120xc2x0 C.
The molar ratio of III to XIII may be between 1 and 5, better still between 1 and 3. In order to increase the reaction kinetics and the yield, this reaction can advantageously be carried out in the presence of an acid catalyst, such as para-toluenesulphonic acid.
By way of example, one equivalent of XIII is reacted with 1 to 3 equivalents of the ketone III in refluxing toluene in the presence of from 0.2 to 2.2 equivalents of para-toluenesulphonic acid in Dean-Stark apparatus for 6 to 24 hours.
When R18 or R19 represents a radical which is a precursor of Ra, the reaction of XIII with III will be followed by a step of converting the resulting compound into the compound of formula I.
The operating conditions for this conversion will be readily determined by a person skilled in the art using his or her general knowledge.
The compounds of XIII type can be synthesized, for example, according to the schemes described in H. P. Kaufmann et al., Chem. Ber., 1959, 2810.
For the synthesis of the compounds of formula I in which X represents C and Y represents xe2x80x94NRaxe2x80x94, process G below may be carried out.
Process G
Compound XIV below: 
in which R2 to R7 are as defined for I and R20 has one of the meanings given for R17 above, is reacted with the ketone of formula III: RCOxe2x80x94R1 in which R and R1 are as defined for formula I.
The compounds of formula I in which Ra is other than H can be obtained from the corresponding compounds of formula I in which Ra is H by N-alkylation. The N-alkylation will be carried out in a manner which is known per se to those skilled in the art, for example by the action of an alkyl iodide or a dialkyl sulphate.
The operating conditions for the reaction of compound XIV with the ketone III are those conventionally used in the technique for this type of reaction. They may be derived from any of the following publications:
W. Schneider et al., Arch. Pharm. Ber. Dtsch. Pharm. Ges., 1966, 299, 997
G. Bernath et al., Pharmazie, 1983, 38, 2, 89
E. D. Bergmann et al., J. Chem. Soc., 1963, 3736
E. Biekert et al., Chem. Ber., 1961, 1664
In general, the operating conditions prescribed in the case of process F may be suitable.
By way of example, the amino alcohol XIV can be reacted with 1 to 3 equivalents of the ketone III in refluxing toluene in the presence of from 0.2 to 1.2 equivalents of para-toluenesulphonic acid in Dean-Stark apparatus for 4 to 10 hours.
The amino alcohols XIV can be prepared, for example, according to the schemes described in C. A. Grob et al., Helv. Chem. Acta, 1972, 501.
The publications cited above also illustrate the preparation of the amino alcohols of formula XIV.
The compounds of formula I in which X and Y represent S may be prepared by carrying out process H below.
Process H:
According to this process, the dithiol of formula XV: 
in which R2 to R7 are as defined for formula I, is reacted with the ketone of formula III: RCOxe2x80x94R1 in which R and R1 are as defined above for I.
The process will preferably be performed in a polar aprotic solvent such as an ether at a temperature of from 15 to 30xc2x0 C., better still from 18 to 25xc2x0 C., in the presence of a slight excess of the ketone III.
The molar ratio of compound XV to compound III is usually between 1 and 2, preferably between 1.3 and 1.7.
More generally, reference may be made to
I. Shahak et al., J. Chem. Soc. 1966, 1005
G. A. Olah et al., Synthesis, 1981, 282 for the implementation of this reaction.
By way of example, compound XV is reacted with 1.2 equivalents of the ketone III in dioxane at 20xc2x0 C. until the reaction is complete (from 5 minutes to 2 hours are generally sufficient).
The dithiols of formula XV are prepared in a manner which is known per se and exemplified in particular in J. Houk et al., J. Amer. Chem. Soc. 1987, 6825-6836 and E. L. Eliet et al., J. Amer. Chem. Soc., 1976, 3583-3590.
The hypolipidaemic and hypoglycaemic activity of the compounds of the invention result from their capacity to activate the PPARxcex1 and PPARxcex3 type receptors. The activation of the PPARxcex1 receptors has been illustrated using rat primary hepatocytes in the case of the compound of Example 4.
More specifically, the effects of the compounds of the invention on the expression of genes involved in lipid metabolism (Acyl CoA oxidase) or lipid transport (apo A-I, apo C-III) were studied in the model of rat hepatocytes in primary culture obtained according to a modification of the initial procedure of Berry and Friend (Berry M, Friend D. 1969. J. Cell. Biol. 43: 506-520) described previously (Berthou L, Saladin R, YaQoob P, Branellec D, Calder P, Fruchart J C, Denxc3xa8fle P, Auwerx J, Staels B. 1995. Eur. J. Biochem.: 232, 179-187). These genes are modulated in a coordinated manner by PPAR and thus represent good markers of the activation of the PPARxcex1 mainly expressed in the hepatic tissue (Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W; 1995. Endocrinology: 137, 354-366). The hepatocytes were isolated by xe2x80x9cin situxe2x80x9d hepatic infusion of collagenase (Wistar rats whose weight ranges between 200 and 250 g), homogenization of the tissue, filtration through Nylon, centrifugation at low speed and inoculation at a rate of 107 cells per dish (if the viability estimated by the Trypan blue test exceeds 90%). The cells were stimulated from the start of inoculation (compounds dissolved in DMSO) in L15 culture medium supplemented with 10% foetal calf serum, 0.2% (mass/volume) of bovine serum albumin (BSA), 3 g/l of glucose and 26 mM bicarbonate, 2 mM glutamine and antibiotics. After incubation for 24 hours at 37xc2x0 C. in a humid atmosphere of 5% CO2/95% air, the cells were lysed in guanidine thiocyanate solution, the RNAs extracted with phenol (pH4/chloroform, assayed by spectrophotometer, transferred onto a membrane (Dot blot, Northern blot) and hybridized with specific molecular probes according to the procedures described previously (Staels B, Van Tol A, Andreu T, Auwerx J; 1992. Atherioscler. Thromb. 12: 286-294). The cDNA of the clone 36B4 coding for the human PO acidic ribosomal phosphoprotein (Masiakowski P, Breathnach R, Bloch J, Gannon F, Krust A, Chambon P; 1982. Nucl. Acids Res. 10: 7895-7903), whose tissue expression is stable, was used as control probe.
The cDNA probes were labelled with 32P using random primers by means of the kit sold by Boehringer Mannheim. The membranes were hybridized with 1.5xc3x97106 cpm/ml of each probe according to the procedure described previously (Staels B, Van Tol A, Andreu T, Auwerx J; 1992. Atherioscler. Thromb. 12: 286-294). They were washed once in 0.5xc3x97SSC buffer and 0.1% SDS at room temperature for 10 min and twice in the same buffer at 65xc2x0 C. for 30 min, and then autoradiographed (X-OMAT-AR film, Kodak). The autoradiographs were analysed by densitometry (Biorad GS670 densitometer).
The effects of the compound of Example 4 on the hepatic gene expression were studied.
The hepatic expression of the ACO gene is increased by a 24-hour treatment with the compound of Example 4 (25 xcexcM). This response is typical of the effects observed previously (Berthou L, Saladin R, YaQoob P, Branellec D, Calder P, Fruchart J C, Denxc3xa8fle P, Auwerx J, Staels B. 1995. Eur. J. Biochem.: 232, 179-187) (Staels B, Vu-Dac N, Kosykh V. A., Saladin R, Fruchart J. C., Dallongeville J., Auwerx J.; 1995. J. Clin. Invest. 95: 705-712) when the hepatocytes are treated with fibrates which are ARxcex1 ligands and activators (Devchand P, Keller H, Peters J, Vasquez M, Gonzales F, Wahli W.; 1996. Nature; 384: 39-43). These results suggest that the compounds of the invention act via PPARxcex1. Similar results were reproduced in two independent experiments.
Expression of the mRNAs coding for the ACO genes in rat hepatocytes in primary culture treated for 24 hours with the compound of Example 4 (25 xcexcm).
The values are expressed relative to the base value (%).
Activation of the PPARxcex3 was similarly demonstrated in the case of the compound of Example 4.
Analysis of the activation of PPARxcex3 is based on the transfection of a DNA allowing the expression of a reporter gene (CAT (chloramphenicol acetyltransferase)) under the control of PPAR in cells which express PPARxcex3. The reporter plasmid J3TkCAT described previously (Fajas L, Auboeuf D, Raspxc3xa9 E, Schoonjans K, Lefebvre A. M., Saladin R, Najib J, Laville M, Fruchart J. C., Deeb S, Vidal-Puig A, Flier J. Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272: 18779-18789) comprises three copies of the PPAR response element for human apo A-II gene which are cloned upstream of the promoter for the thymidine kinase gene of the herpes simplex virus in the plasmid pBLCAT4 (Staels B, Vu-Dac N, Kosykh V. A., Saladin R, Fruchart J. C., Dallongeville J, Auwerx J.; 1995. J. Clin. Invest. 95: 705-712). The cells used are the green monkey CV1 cells and COS cells transformed by the SV40 virus and which express PPARxcex3 (Forman B, Tontonoz P, Chen J, Brun R, Spiegelman B, Evans R.; 1995. Cell. 83: 803-812). These cells were inoculated at a rate of 300,000 cells per dish (dishes 5 cm in diameter) and transfected with 500 ng of reporter DNA according to a process described previously (Fajas L, Auboeuf D, Raspxc3xa9 E, Schoonjans K, Lefebvre A. M., Saladin R, Najib J. Laville M, Fruchart J. C., Deeb S, Vidal-Puig A, Flier J, Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272: 18779-18789). After 5 to 6 hours, the cells were washed twice with PBS and incubated for 36 hours in fresh culture medium (DMEM) containing 10% foetal calf serum. After transfection, the cells were lysed and the CAT activity was measured according to the procedure described previously (Fajas L, Auboeuf D, Raspxc3xa9 E, Schoonjans K, Lefebvre A. M., Saladin R, Najib J, Laville M, Fruchard J. C., Deeb S, Vidal-Puig A, Flier J, Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272: 18779-18789). It is expressed relative to the control value.
The effects of the compound of Example 4 are given in FIG. 1.
The activity of the CAT reporter gene of Cos cells transfected with the J3TkCAT construct is increased when these cells are incubated in the presence of the compound of Example 4. On the other hand, when the Cos cells are transfected with the pBLCAT4 plasmid lacking the PPAR response element, the compound of Example 4 is inactive.
In FIG. 1, T represents the control value for each reporter (TkCAT or J3TkCAT).
In a final test, the hypolipidaemic and hypoglycaemic activity of the compound of Example 4 was evaluated in db/db mice.
Two-month-old db/db mice were treated orally for 15 days with the compound of Example 4 (100 mg/kg/day). Each study group comprises seven animals. After three days (D3) and 15 days (D15) of treatment, retro-orbital samples were taken after light anaesthesia and without fasting.
The following measurements were taken:
assay of the glycaemia (glucose oxidase) at D3 and D15 and of the lipid parameters on the sera at D15 (COBAS): triglycerides, total cholesterol (CHOL), HDL cholesterol (HDL-C) and free fatty acids (FFA) (assay kit from BioMxc3xa9rieux and Wako Chemicals).
The results obtained are given in the table below. The measurements given in this table are average valuesxc2x1standard error.
A subject of the invention is also a pharmaceutical composition comprising an effective amount of at least one active principle chosen from a compound of formula I as described above, a compound of formula XVI: 
in which R and R1 together form one of the radicals: 
R2, R3, R5 and R7 represent a hydrogen atom;
X and Y represent an oxygen atom;
R4 represents a methyl; and
R6 represents a hydrogen atom or a methyl group;
and a pharmaceutically acceptable salt of these compounds, in combination with at least one pharmaceutically acceptable vehicle.
These compositions can be administered orally in the form of immediate-release or controlled-release granules, gelatin capsules or tablets, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or locally in the form of a solution, cream or gel.
A solid composition for oral administration is prepared by adding a filler and, where appropriate, a binder, a crumbling agent, a lubricant, a dye or a flavour enhancer to the active principle and by shaping the mixture into a tablet, a coated tablet, a granule, a powder or a capsule.
Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of binders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened plant oils. The dye can be any of those authorized for use in medicinal products. Examples of flavour enhancers include cocoa powder, mint in herbal form, aromatic powder, mint in oil form, borneol and cinnamon powder. Needless to say, the tablet or granule can be suitably coated with sugar, gelatin or the like.
An injectable form containing the compound of the present invention as active principle is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent and/or a preserving agent, and by converting the mixture into a form for intravenous, subcutaneous or intramuscular injection, according to a standard process. Where appropriate, the injectable form obtained can be freeze-dried by a standard process.
Examples of suspending agents include methylcellulose, polysorbate-80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate.
Examples of solubilizing agents include castor oil solidified with polyoxyethylene, polysorbate-80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.
In addition, the stabilizer includes sodium sulphite, sodium metasulphite and ether, while the preserving agent includes methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic], cresol and chlorocresol.
The invention is also directed towards the use of an active principle chosen from a compound of formula I as defined above, a compound of formula XVI as defined above, a compound of formula XVII: 
in which
X and Y represent an oxygen atom;
R4, R5, R6 and R7 represent a hydrogen atom;
R represents pyridyl, piperidyl; pyridyl optionally substituted with one or more radicals chosen from a radical Z as defined above for formula I and a (C1-C7)alkylene chain; and piperidyl optionally substituted with one or more radicals chosen from a radical Z as defined above and a (C1-C7)alkylene chain; and
R1 represents phenyl optionally substituted with one or more radicals W as defined above for formula I; and a pharmaceutically acceptable salt of these compounds, for the preparation of a medicinal product intended to prevent or treat dyslipidaemia, atherosclerosis and diabetes.